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• W4384523148 abstract "To date, pathogenic variants in 14 genes have been identified to be responsible for autosomal recessive congenital ichthyosis (ARCI), including NIPAL4 and PNPLA1.1, 2 Impaired barrier function in ARCI patients might cause dysregulation of cytokines and skewing towards the T-helper (Th) 17 pathway resembling the immunophenotype of psoriasis and suggests a potential therapeutic approach with anti-interleukin(IL)-17 therapy.3 Furthermore, the inhibition of IL-4 and IL-13 in the Th2 pathway was shown effective in decreasing pruritus in atopic dermatitis (AD) and Netherton syndrome.4, 5 We hypothesized that targeted therapy of IL-17A may improve erythema and scaling in ARCI patients and anti-IL-4/IL-13 might be promising to improve pruritus. We performed a retrospective analysis and report the clinicogenetic features of five unrelated patients (patients I–V) with three different NIPAL4 variants, and seven patients (patients VI–XII) from four families harbouring three different PNPLA1 variants (Figure 1; Table 1). Treatment response was assessed by the Ichthyosis Area and Severity Index (IASI), Visual Index for Ichthyosis Severity (VIIS), Investigator Global Assessment (IGA), Numeric Rating Scale (NRS) itch (last 7 days) and Dermatology Life Quality Index (DLQI). Patients I–III with NIPAL4 variants were treated with secukinumab (Figure 1c–h). Patients I and III continued their previous treatment with acitretin, 10 and 25 mg/day, respectively. Secukinumab resulted in initial improvement (IASI-total, VIIS) in all three patients after 8 weeks of treatment, but improvement on erythema (IASI-E) and scaling (IASI-S) varied thereafter. To improve treatment efficacy, the interval of secukinumab was shortened, in Patient I to 3-weekly after 4 months and 2-weekly after 7 months and in Patients II and III to 3-weekly after 2 months. Despite this, treatment was discontinued in Patients I and II due to inefficacy after 14 and 7 months, respectively. Patient III experienced sustained clinical improvement after 3 months with further improvement after 10 months; consequently, his acitretin dosage was reduced to 20 mg/day. In all three patients, IGA, DLQI and NRS-itch results were consistent with the degree of IASI improvement or deterioration. The varying effects of secukinumab in these patients are consistent with a recently reported randomized placebo-controlled trial in 20 ichthyosis patients including ARCI that showed that Th17 biomarkers did not significantly decrease, suggesting that skewing of the Th17 pathway alone is not sufficient to explain the pathogenesis of ichthyosis.6 Moreover, another study reported that skewing of the Th17 pathway may reflect a response to the altered microbial colonization in ichthyosis.7 Interestingly, since not only IL-17A but also IL-17F is highly expressed in the skin of ichthyosis patients, anti-IL-23 or specific anti-IL-17A/IL-17F therapy could possibly result in improved treatment efficacy. Furthermore, the recommended doses of anti-IL-17A for ichthyosis remain elusive. Recent studies in psoriasis have suggested that early initiation of biological therapy might be more effective by altering the natural disease course.8 Likewise, this therapeutic window of opportunity may be of importance in ichthyosis patients.6 Patients VIII and IX with PNPLA1 variants were treated with dupilumab due to the earlier diagnosis of AD and severe itch (Figure 1d–h). Patient VIII presented with an additional loss-of-function variant in FLG, which might explain the patients' phenotype with additional features of AD. Patient VIII reported improvement in NRS-itch from 8 to 0 after 8 weeks of treatment. Patient IX had been treated with dupilumab prior to our consultation for 2 years at a different centre with an improvement in NRS-itch from 9 to 0. IASI scores were only available for Patient VIII and showed no considerable improvement. IL-4 and IL-13 have been shown to play an important role in chronic itch9 and to improve pruritus in AD and NS.4, 5 Although in our study dupilumab did not improve the clinical severity in two patients with PNPLA1 variants, it does confirm a potential role to improve pruritus in PNPLA1 and possibly other ichthyoses. No adverse events were observed for secukinumab or dupilumab. Genotype–phenotype correlations have not been established for NIPAL4 and PNPLA1 variants, and variability in phenotype was also confirmed in this study (Figure 1a,b, Table 1).10, 11 Although initially proposed that yellowish palmoplantar keratoderma might be indicative of NIPAL4 variants, our study showed diverse palmoplantar presentations (Table 1) corresponding to more recent literature.11, 12 Palmar hyperlinearity was present in four cases and is a known finding in patients with PNPLA1 variants.10 Striking interfamilial variability was observed in two brothers with PNPLA1 variants (Patients VI and VII). Patient VI developed erythrokeratoderma-like lesions, whereas Patient VII developed a very mild phenotype with localized fine white scales (Figure 1b). Whole exome sequencing in patient VI excluded variants in other ichthyosis-related genes, including genes associated with erythrokeratoderma variabilis phenotypes.13 With this study, we show clinical variability in patients with NIPAL4 or PNPLA1 variants and variable effects of secukinumab and dupilumab. Future research should provide more clarity on the potential of biological treatment for ARCI. c.398G>T p.(Gly133Val); c.527C>A p.(Ala176Asp) Compound heterozygous DUF803 domain Missense; Exon 4 Missense Thick caseous vernix Erythema after few months Progression of scaling and PPK Generalized white to light-brown coarse scales Dirty neck sign + Erythema Scaling Palmar: focal PPK with erythema, blisters and fissures Plantar: mild maceration Hypohydrosis Only transpiration of forehead c.527C>A p.(Ala176Asp) Homozygous Exon 4 Missense Collodion Erythroderma Generalized white to light-brown coarse scales Sharply demarcated keratotic plaques + At birth + Erythema Scaling c.527C>A p.(Ala176Asp) Homozygous Exon 4 Missense Erythroderma Scaling Thick caseous vernix Progression childhood Improvement in summer PPK since 14 years old Widespread erythematous plaques Dorsal aspects of the hands affected + Erythema c.527C>A p.(Ala176Asp) Homozygous Exon 4 Missense + Mild + Erythema Palms: PPK striata Plantar: yellowish confluent PPK c.889G>A p.(Gly297Arg) Homozygous Exon 4 Missense Generalized fine white scaling Erythematous plaques on dorsal hands and feet c.700C>T p.(Pro234Ser) Homozygous Exon 4 Missense Collodion Scaling Erythroderma Blisters Generalized white fine scales. At a younger age also light-brown thicker scales + Scaling c.700C>T p.(Pro234Ser) Homozygous Exon 4 Missense Scaling Erythroderma Cryptorchidism WES – skin panel c.704C>T p.(Pro235Leu) Homozygous FLG c.2282_2285del Heterozygous Exon 4; Missense Exon 3 Deletion + Erythema Scaling Plantar diffuse PPK with erythema Palmar hyperlinearity + c.704C>T p.(Pro235Leu) Homozygous Exon 4 Missense Exon 4 Missense c.488C>T p.(Pro163Leu) Homozygous Exon 3 Missense Collodion Scaling Erythroderma Erosions Generalized white to light-brown coarse lamellar scales Fissures + Ectropion and eclabion at birth c.700C>T p.(Pro234Ser) Homozygous Exon 4 Missense Variable 2× year flares of erythema Worsening in winter Generalized, fine white scales More prominent on lower legs None. We thank the patients for their involvement. This project is part of the European Reference Network-SKIN subthematic group Ichthyosis and Palmoplantar Keratoderma (https://ern-skin.eu). Treatment with secukinumab was provided on an individual patient basis via the Novartis-Managed Access Program. AG has received consulting fees from Novartis and Sanofi outside the submitted work. AG is also a stakeholder of Novartis and Sanofi. The other authors declare no conflict of interest related to this manuscript. The patients in this manuscript have given written informed consent to publication of their case details. This study received approval from the Medical Ethics Committee of the Maastricht University Medical Centre+ (METC 2020-2268A2)." @default.
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• W4384523148 date "2023-07-24" @default.
• W4384523148 modified "2023-09-27" @default.
• W4384523148 title "Expanding the molecular and clinical spectrum of autosomal recessive congenital ichthyosis caused by pathogenic variants in <i>NIPAL4</i> and <i>PNPLA1</i> and evaluation of novel therapeutic interventions" @default.
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• W4384523148 doi "https://doi.org/10.1111/jdv.19340" @default.
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